title: Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.
abstract: BACKGROUND
  Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment.
  
  
  METHODS
  We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells.
  
  
  RESULTS
  Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments.
  
  
  CONCLUSIONS
  Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.
authors.affiliation: Medical Oncology Department of Jinling Hospital, Medical school of Nanjing University, Nanjing, People's Republic of China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Shi
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Yitian
authors.initials: Y
authors.lastname: Chen
authors.forename: Haizhu
authors.initials: H
authors.lastname: Song
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
authors.forename: Guichun
authors.initials: G
authors.lastname: Huang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D048430:Cell Shape; D003131:Combined Modality Therapy; D055612:Cytokine-Induced Killer Cells / Q000276:immunology* / Q000637:transplantation; D043169:Endostatins / Q000627:therapeutic use*; D006801:Humans; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000098:blood supply / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D055806:Microvessels / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology; D013154:Spleen / Q000276:immunology; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins